Neurology® Podcast

Dr. Dara Albert talks with Dr. Bruce Cohen about the future of child neurology residency training, exploring current models, consensus areas, and challenges in evolving the curriculum to meet future healthcare needs.
Read the related article in Neurology® Education.
Disclosures can be found at Neurology.org.

Dr. Tesha Monteith talks with Dr. Tamara Pringsheim about the updated American Academy of Neurology (AAN) and American Headache Society (AHS) guidelines on pharmacologic treatment for migraine prevention in adults. 
Read the related article in Neurology®.
Disclosures can be found at Neurology.org. 
Show transcript: 
Dr. Jose Merino (00:08):
This is Jose Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.
Dr. Tesha Monteith (00:23):
Hi, this is Tesha Monteith with the Neurology Podcast. I'm excited to talk to you today about the update in Migraine Guideline: Pharmacologic Treatment for Migraine Prevention in Adults: Practice Guideline Recommendations, a report of the American Academy Neurology Guidelines Subcommittee, and the American Headache Society. Since the last guideline in 2012, there's been a lot of new advances, including the introduction of CGRP inhibitors for acute and preventive treatment.
(00:53):
With me to discuss is the lead author, Tamara Pringsheim, a neurologist at the Department of Clinical Neurosciences, Psychiatry, Pediatrics, and Community Health Sciences at the University of Calgary. How are you, Tamara?
Dr. Tamara Pringsheim (01:06):
Great. Thank you for asking me to talk to you about this.
Dr. Tesha Monteith (01:09):
Why don't you tell me a little bit about yourself and how you got involved in this work?
Dr. Tamara Pringsheim (01:14):
Sure. I've been working as a methodologist for the American Academy of Neurology Guidelines Subcommittee for a number of years, since 2015. Prior to that, I was a member of the guideline development subcommittee from 2011. I've worked on a number of different guidelines across neurological conditions.
Dr. Tesha Monteith (01:36):
Great. So how do these new guidelines compare, just broadly speaking, with the older guidelines?
Dr. Tamara Pringsheim (01:43):
I guess since the last guidelines were published more than 10 years ago, we've had changes to our methodological process. We had a major update to our guideline process manual in 2017, and guideline methodology has continued to evolve over that time period. And as well, a number of targeted treatments for migraine have come out. So there's been an explosion of evidence, particularly in the last five to seven years. And so we have a whole new class of medications available for migraine prevention, which really target our underlying understanding of the condition, whereas most of the other medications were discovered through serendipity.
Dr. Tesha Monteith (02:33):
So I know that you reviewed over 200 randomized controlled trials. And so how was the quality or confidence of the evidence determined?
Dr. Tamara Pringsheim (02:47):
With our process, we start by rating risk of bias for every article. This basically gets at a number of different features related to the clinical trial methodology and reporting, and it helps us determine how confident we are in the evidence. In order for us to be highly confident that the results that we are seeing reflect the truth, we typically need to have at least two Class 1 studies for any intervention outcome pair. The effect size estimate also has to meet a certain threshold in terms of the effect size and the precision surrounding that estimate. So if we feel that based on what the panel decides in terms of what is the minimal clinically important difference between an intervention and placebo, that will help us determine our confidence in the evidence.
(03:51):
So there's this critical coming together of the number of studies, the quality of studies, the effect size, and the precision of the evidence that helps us determine our confidence in the evidence. And all of this is done behind the scenes using a very algorithmic approach so that these rules are faithfully applied across the different interventions we're looking at. This complexity makes it hard for people to understand why certain drugs land in a certain area, but it's one of the things that we do to make this process standardized and rigorous.
Dr. Tesha Monteith (04:37):
So I do want to talk to you about that, where drugs have landed. One newer thing was that the review was not just episodic migraine, but also chronic migraine.
Dr. Tamara Pringsheim (04:47):
Yes.
Dr. Tesha Monteith (04:48):
Were there important differences in the strength of evidence between these populations?
Dr. Tamara Pringsheim (04:53):
One thing that's really important to remember is that the use of the term chronic migraine is fairly new. So a lot of the trials of the older headache preventive medications were done in the 80s and the 90s. And at this time, there wasn't a definition which distinguished chronic migraine in particular. So a lot of the trials for amitriptyline, for example, were not done in a purely episodic or chronic migraine population. And so this really contrasts with the newer studies where these populations were well-defined. And so we're going to have higher quality evidence or evidence specifically for chronic migraine with the new drugs, whereas for the old drugs, we won't have that.
Dr. Tesha Monteith (05:50):
Let's get into the preventive treatments that had the strongest level of evidence for episodic migraine.
Dr. Tamara Pringsheim (05:57):
We had high confidence in the evidence for two of the CGRP medications, erenumab and galcanezumab. Again, these high confidence in the evidence statements are based on the fact that for both these drugs, there were multiple Class 1 studies showing that they were efficacious. And the effect size was in the range that was pre-specified. So the lower level of the 95% confidence interval was clearly higher than what we decided was the minimal clinically important difference. Both these drugs, one had two Class 1 studies, one had three Class 1 studies, so we could be very highly confident that these two medications were efficacious.
(06:50):
Now for the moderate confidence drugs, we have a longer list for episodic migraines. So it includes atogepant, eptinezumab, fremanezumab, propranolol, rimegepant, topiramate, and valproate, and then a slightly longer list for the low confidence drugs. So amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan.
(07:18):
And for this outcome, I'm specifically talking about episodic migraine headache days. Now, one of the layers of complexity, again for this guideline, is that we had a few different outcomes that we were looking at. So the two main outcomes we were looking at were the headache frequency, the change in the number of headache days, but also the 50% responder rate. That's the proportion of people in the treatment group who had at least a 50% reduction in their headache frequency. And some drugs would make it for one endpoint, but not the other. And this is an important nuance that, again, adds complexity to our data synthesis.
Dr. Tesha Monteith (08:06):
And what about for chronic migraine?
Dr. Tamara Pringsheim (08:08):
So for chronic migraine, for the number of headache days, we had high confidence for fremanezumab, galcanezumab and onabotulinumtoxinA, and moderate confidence for atogepant, eptinezumab, erenumab, topiramate, rimegepant, and valproate. We didn't have any medications that were in the low confidence in the evidence category.
Dr. Tesha Monteith (08:33):
Oftentimes in the newer clinical trials, we're looking at change in monthly migraine days, but interesting that you looked at headache days.
Dr. Tamara Pringsheim (08:42):
Yeah. So another difficulty is that there's not always consistency in what's reported. So some trials would report headache days and some trials would report migraine days per month. Wherever possible, we use the change in the number of days with migraine. And where this was not present, we would use headache days.
Dr. Tesha Monteith (09:08):
Now, a drug that we use very often in clinical practice is rimegepant, which has a dual benefit of acute attack treatment as well as prevention. And that was rated as low confidence, but in a recent International Headache Society, Italian guidelines, that was noted as moderate quality evidence, strongly in favor of. What do you think that discrepancy was about? Is that a matter of outcomes or?
Dr. Tamara Pringsheim (09:38):
This guideline includes clinical trials that were published up until June of 2024. And so at that time, the only trial of rimegepant versus placebo that was published was in a population of patients that had episodic or chronic migraine. The population was combined. And so we only have one study. And as I was explaining at the beginning, in order for us to have high confidence in the evidence, we have to have at least two Class 1 studies and the minimal clinically important difference has to meet a certain threshold. So for rimegepant in June of 2024, there's only one study published versus placebo. So the highest possible confidence in the evidence we could have for rimegepant based on the fact that just one study would be moderate.
(10:38):
The reason why it's not listed in recommendation 3A as high or moderate confidence is because while we had moderate confidence in the evidence for rimegepant on the number of headache days, we had low confidence in the evidence for the 50% responder rate. And that's because for the 50% responder rate, it did not meet the pre-specified cutoff with respect to the minimally clinically important difference.
(11:11):
So again, it's a small nuance in the evidence, but for an evidence-based guideline, we really pay attention to these things. I know it makes it complex and hard for people who are not immersed in the evidence to understand. This is part of the rigor. There's a temptation to oversimplify things so that it's easy to understand, but that's really one of the strengths of the AAN process is that we take the evidence very seriously. We are truly evidence-based. We are going through every data point very carefully, and so that you should feel confident when you see that we've rated these medications as a higher moderate confidence, that we've really looked and evaluated these data points very carefully.
Dr. Tesha Monteith (12:01):
We can say that different guidelines have different outcomes. And to your point, it's more than just the data. It's your pre-specified process that then led to those recommendations, right?
Dr. Tamara Pringsheim (12:14):
Yeah. And I feel pretty confident that if we were to update the evidence, including the last two years, that rimegepant would move up, right? Because just looking even quickly now, we can see that since 2024, there have been several additional studies published. So now we wouldn't just be basing our evidence review on one placebo controlled study. There have been several more, the medications FDA approved.
Dr. Tesha Monteith (12:44):
Right.
Dr. Tamara Pringsheim (12:45):
I don't think anyone should change their practice based on this and people should be using rimegepant. That's not the message that we're trying to send.
Dr. Tesha Monteith (12:54):
That's really important.
Dr. Tamara Pringsheim (12:55):
Yes. We are not on a campaign to say that rimegepant is not a treatment option. As you can see, it is listed and it is in the guidelines. It's just based on the data we had available, we had low confidence in one of the outcomes, the 50% responder rate. So I hope that makes sense.
Dr. Tesha Monteith (13:14):
Yeah, I think it makes sense. It's the processes, it's a 2017 guideline manual, and that does make sense. So thank you for that clarification because a lot of our clinicians will be asking questions about this.
Dr. Tamara Pringsheim (13:26):
I mean, the same goes for another drug, candesartan is the other one.
Dr. Tesha Monteith (13:30):
Yeah. Candesartan recently had a paper published in the Lancet.
Dr. Tamara Pringsheim (13:33):
Yes.
Dr. Tesha Monteith (13:33):
And it did well, and people are using candesartan.
Dr. Tamara Pringsheim (13:38):
Yes. Yes, exactly. I prescribe candesartan for migraine prevention. At the time we did the evidence review, we had a couple of positive studies, a couple of negative studies. And when we put the data together, it came out as very low confidence because there's a discrepancy. And then we have a huge trial published that is a positive study, but it came out in 2026. It was not part of our evidence review. We don't say anywhere in the guideline, don't use candesartan, right? We don't say that. We highlight the drugs for which we have the confidence in the evidence and put them in there. But we need to remember that new drugs are coming out all the time and that they didn't factor into our decision making.
(14:26):
So again, I hope that people don't read the guideline and say, "Oh my God, I can't use candesartan." That's not true.
Dr. Tesha Monteith (14:33):
So one thing I want to look at is quality of life outcomes. That was something also not seen in the first or the 2012 guidelines. And so how did you look at quality of life outcomes and how should we consider them?
Dr. Tamara Pringsheim (14:47):
Yeah, so we wanted to make sure that we incorporated patient reported quality of life outcomes in the guideline, recognizing that this is very important. And the newer trials of the more recent medications have been incorporating patient reported quality of life outcomes in their clinical trials. This adds overall credibility that we are incorporating into our decision-making evidence that not only are patients' number of headache days decreasing, but their quality of life is improving because that's important to patients and hence is important to us.
(15:31):
So we used outcomes from validated measures of migraine related quality of life. So there's the MIDAS, there's the HIT-6, and there's something called the migraine specific questionnaire, which has three subscales. One is emotional function, one is role function preventive, and one is role function restriction. And then a few studies use something called the migraine physical function impact diary. So those were the main instruments that we looked at. And again, we had a pre-specified minimally clinically important difference on these instruments that we looked at.
(16:19):
And we had a reasonable amount of data, not as much data as we had for headache days or the responder rate, but certainly again, for the CGRP antagonists, we had high confidence in the evidence for galcanezumab, for example, in episodic migraine. And for chronic migraine, we had moderate confidence in the evidence for a number of medications including topiramate and onabotulinumtoxinA. So these quality of life measurements seem to be increasingly used in our modern clinical trial era.
Dr. Tesha Monteith (17:07):
Great. Another question is just thinking about some of the limitations of this work. There were very few high quality head-to-head trials. How does that limit your comparative effectiveness data?
Dr. Tamara Pringsheim (17:19):
This is a major issue that most, but not all of the head-to-head trials were investigator-led. Many were done a very long time ago before the modern clinical trial era, and so the quality of these studies was low. And also they were not non-inferiority studies. So basically the only question they could answer is whether drug A is better than drug B based on their trial protocol and methodology. And for most of the comparisons, we have very low quality evidence, so we really cannot support or refute that drug A is better or worse than drug B. So we can't really say anything. There were a few instances where we could say that drug A is better than drug B, but it's low confidence evidence, very few comparisons.
(18:17):
Some evidence is emerging so that some of the CGRP drugs are being compared to some of the older drugs now with the hope that we can prescribe these sooner to migraine patients. That evidence will probably emerge in the coming years.
Dr. Tesha Monteith (18:31):
And another question is how should these guidelines be incorporated in clinical practice also while balancing tolerability, comorbidities, patient preference, reproductive considerations, access, and costs?
Dr. Tamara Pringsheim (18:47):
So we have the evidence synthesis. So you can say, okay, this is the evidence. These are the effect sizes. This is the number of studies to support this outcome, that outcomes. You have the details in the systematic review, right? And then how do you take those details and apply them in the practice? And that's the art of medicine. And we don't make decisions without our patients. All of our decisions are collaborative. I say to my patients, "It's my job to tell you what your options are. It's your job to discuss these options with me and for us to make a decision together regarding which one is the best for you in your situation."
(19:30):
And that's what we're trying to do in the recommendations. In the recommendation statements, you'll see that in this specific situation, this might be a better choice. We talk a lot about when you're going to decide to even start a preventive and the importance of shared decision making, that those are our first two sets of recommendations. Recommendations one and two are about those things.
(19:56):
And then our recommendation three statements just tries to gently offer some advice on when you should think about which medication, where efficacy is the priority, tolerability is the priority, long-term harms, cost. Cost is a really tricky one because cost really depends on the person's specific pharmaceutical formulary plan and healthcare insurance. I know that for some patients, their insurance plans require a certain number of oral medications to be tried before an injectable like a botulinum toxin or a subcutaneous medication or one of the newer medications can be prescribed.
Dr. Tesha Monteith (20:41):
So you put a lot of work in this, your team, the American Academy of Neurology, the American Headache Society, outstanding work. What should we take away from this?
Dr. Tamara Pringsheim (20:52):
I think that we should take away that a lot of work is being done by headache neurologists and neuroscientists who are interested in headache to develop new treatments for people with migraine. I think that the CGRP drugs are a major advance and that now we have many new medications that are specifically designed for migraine treatment and these treatments are changing people's lives for the better. I think it's brought new hope to people with migraine and it's an exciting time to be a clinician who treats patients with migraine when you have several new medications where the companies have invested the time to do the research, do well-designed clinical studies, and that we can feel confident that these medications are helping our patients.
Dr. Tesha Monteith (21:51):
Excellent. I couldn't have said that better. Thank you again for your work and your time and for being on our podcast.
Dr. Stacey Clardy (22:00):
This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on the podcast app for any neurology specific topics.

Dr. Justin Abbatemarco talks with Dr. Irene Cortese about recent advances in the treatment of progressive multifocal leukoencephalopathy (PML), focusing on immune-based therapies like virus-specific T cells and immune checkpoint inhibitors. 
Read the related article in The New England Journal of Medicine. 
Disclosures can be found at Neurology.org. 
Show transcript: 
Dr. José Merino:
This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening, and have a great week.
Dr. Justin Abbatemarco:
Hello and welcome. This is Justin Abbatemarco with the Cleveland Clinic here with Irene Cortese to discuss an update on progressive multifocal leukoencephalopathy treatment in light of a New England Journal of Medicine correspondence, Resolution of PML After Treatment with Virus-Specific T Cells and HCT. Irene directs the Experimental Immunotherapeutics Unit at NINDS. Hello and welcome.
Dr. Irene Cortese:
Hi, thank you for the invitation to join you today.
Dr. Justin Abbatemarco:
It's a pleasure to have you on and to talk about this expanding space in rare disease. And maybe if we could start off, can we just take an overview on how PML usually presents and why does it remain so difficult to treat?
Dr. Irene Cortese:
PML, or progressive multifocal leukoencephalopathy, is an opportunistic infection of the brain that is caused by the JC virus. And most of us carry this virus lifelong and without any symptoms, and it really only causes disease when the immune system is significantly compromised and loses the ability to keep it in check. And so when that happens, the virus can gain the ability to infect oligodendrocytes, and this can lead to the rapidly progressive demyelinating infection called PML.
These lesions that develop in PML are typically located in the white matter, and they are most often multifocal. And this leads to the clinical manifestation of a combination of cortical and subcortical symptoms that evolve over weeks to months. And, unfortunately, if immune competence can't be restored quickly, then the disease is fatal within just a few months. And so that's really the core of the problem here, is that there is no effective direct antiviral treatment. And the only thing that works is restoring the immune system ability to control it, but that's often very difficult to do. When it's even possible, it's frequently just not even fast enough.
And so you can see this even in situations where you'd think that we'd have an advantage, for example, in HIV-associated PML, where we do have effective antiretroviral therapy. Even there, restoring immune competence can sometimes just take too long relative to how quickly PML progresses.
And so on top of all that, PML is really quite rare and is also remarkably heterogeneous because it can occur in very different patient populations from HIV to hematological malignancy to genetic immune deficiencies. And this rarity and heterogeneity really make both the diagnosis difficult and also treatment development quite difficult.
Dr. Justin Abbatemarco:
It's such a interesting story, and these different backgrounds really present different challenges. But at these last few years, this has been a success story in some way because we've seen so much effort and research into this rare disease space, which is encouraging. We mentioned this at the top, but there are immune checkpoint inhibitors that have at least been trialed for this T cell exhaustion to see if we can boost the immune system, and then more recently with your work around allogeneic-specific T cells to help clear the infection. What have you taken away from those updates?
Dr. Irene Cortese:
The biggest takeaway is that these two approaches, checkpoint inhibitors and Virus-Specific T Cells, have really transformed the way that we think about PML. So for decades, our only option was really to try to reverse the underlying immune suppressive condition and just hope that the immune system caught up in time. And now we have these two active strategies to try to speed this process up.
Importantly, both these strategies have validated the same core hypothesis that even without a direct antiviral agent, we can improve PML outcomes by restoring effective antiviral immunity. And that said, each of these approaches has real limitations. So first of all, they don't work in all patients. And we have best estimates of success rates somewhere in the 50 to 60% range overall. With checkpoint inhibitors, the fundamental issue is that you're trying to unleash an immune response that has to already be there in some latent or exhausted form.
For example, in patients with very advanced immune compromise where the T-cell compartment is essentially absent, there's just nothing left to invigorate, and so checkpoint blockade is really unlikely to help. And even when they do work, there is a real risk of exacerbating underlying autoimmune disease as well as the risk of leading to immune reconstitution inflammatory syndrome, or IRIS, where inflammation in the central nervous system of this immune system waking up and attacking the infection can actually lead to severe morbidity and even death in some patients.
Virus-Specific T Cells have a whole different set of limitations. These are mostly practical and logistical at this point. Access is really the big one because there are only a handful of centers worldwide that can manufacture Virus-Specific T Cells. And so this just isn't something you can easily do everywhere or quickly. And also, biologically, every virus-specific T-cell product which is made from a different donor is essentially a different drug. And so it's really hard to predict how any given cell product will actually behave in a given patient.
I should also mention that for both these approaches, they truly are still experimental. We don't have any controlled studies, and so most of what we're working from is really retrospective series and case reports. And we definitely have no head-to-head data. And so while we apply general principles estimating residual immune capacity or weighing the risk of exacerbating immune-mediated adverse events, we're really making individualized judgment calls rather than following an evidence-based algorithm.
Dr. Justin Abbatemarco:
And could you talk about those Virus-Specific T Cells? It's not something we use commonly in neurology. How do those work? And have they been used in other spaces successfully that we've been able to maybe apply some of those principles here?
Dr. Irene Cortese:
Yeah. So Virus-Specific T Cells were really first developed in the transplant setting, and they were essentially a way to bridge patients immediately following myeloablation. And in the period of time it took them to fully immune reconstitute a brand new immune system, it was a way to protect them from the common viral infections mostly that can develop in this time period and that led to such high morbidity and even mortality.
And so the way this is done is that you basically take healthy lymphocytes from a healthy donor, and you can train them in vitro by ex vivo expansion and stimulation to basically become professional killers of the particular virus of interest so that, at the end of this expansion period, you basically have a enriched antiviral product that can be adoptively transferred to the patient recipient. And they may not last for a very long time, however, they can, especially with repeated infusions, provide the necessary immunity to bridge until definitive immune reconstitution is achieved.
And so the initial experience with Virus-Specific T Cells was really against the various viruses that are so common in the post-transplant setting, like CMV, EBV, adenovirus, and also BK virus, which is a cousin, let's say, of the JC virus. And over time, the process for manufacturing Virus-Specific T Cells has become more and more streamlined. And so back as in 2015, 2017, we started to realize that perhaps these types of cell products might even be used to treat an acute infection and not just to administer in the setting of a planned transplant.
And so essentially we've done exactly this, basically copied these manufacturing methods from the transplant world to make Virus-Specific T Cells against the JC virus and can then use them to treat PML. I should mention that BK virus is very similar in structure to the JC virus. And for that reason, what we learned early on when we started to apply Virus-Specific T Cells to the treatment of PML was that we could actually use Virus-Specific T Cells that were made against BK virus and successfully treat PML. More recent years, groups have been manufacturing JC virus-specific BST, but those BK Virus-Specific T Cells can still be used to treat PML.
Dr. Justin Abbatemarco:
That's really incredible. And it's so cool when we borrow things from these other fields to help inform rare diseases within neurology space. Maybe it's a perfect segue into the cases report in New England Journal of Medicine where you had two cases with inborn errors of immunity. You've utilized the strategy and then stem cell transplant. Walk us through those cases. What did you see? What did we learn from these that we can apply more broadly?
Dr. Irene Cortese:
Our paper really told the story of our experience of treating these two young men. Both of them had developed PML in the setting of an inborn error of immunity. One of them had DOCK8 deficiency, and he also had Sézary syndrome as a comorbid condition. And the second patient had a CD40 ligand deficiency.
And for both these patients, we basically adopted the same strategy, which was to first try to gain control of the JC viral infection. And once that infection was actually under control, then we went ahead and proceeded to definitive treatment of their underlying genetic immune deficiency, which was transplant in their setting to correct the real root problem that they had.
And what I think was perhaps most instructive in this experience is what happened after transplant in both cases. So transplant obviously involves a period of renewed immune vulnerability, and that's exactly when we feared that the PML might come back, even though we had been able to gain control, at least temporarily, using this adoptive transfer Virus-Specific T Cells.
Fortunately, in these two cases, that didn't happen. And in fact, patient one actually developed IRIS shortly after engrafting with worsening neurological symptoms and also imaging that showed active inflammation, which responded well to steroids. And he's now years out with no evidence of PML or his prior malignancy, which was also treated by the transplant.
The second patient's course was complicated by cryptogenic organizing pneumonia, or COP, which can happen in the post-transplant setting, and did require steroids. And this did cause a transient uptick in the JC viral copy number in the spinal fluid, but this resolved once the steroids were tapered. And this patient also is now several years out with only mild residual neurological deficits. So it's important that for both these patients, the transplant donors, in addition to undergoing collection for the transplant itself, they also underwent a collection to make extra rescue Virus-Specific T-Cell products that we had on hand just in case the PML relapsed post-transplant, which of course was not, in the end, needed.
And so basically, the overall strategy for both these patients was sequential and deliberate. First to establish virus-specific immune control, and only then proceeding to the definitive but higher risk step of transplant with the safety net available in case virus reactivated during that post-transplant period.
Dr. Justin Abbatemarco:
The complexity of these cases, though, and the successful outcome is just incredible. And again, we don't always treat these level of patients, but most neurologists will see PML during their career. How do you think this helps inform this broader field of PML treatment in your mind?
Dr. Irene Cortese:
For me, these two cases really crystallized the idea of immune facilitation as a bridge rather than as a standalone endpoint. For example, in these two patients, Virus-Specific T Cells could not have led to a definitive cure because the underlying immune defect was still there, but they could buy time and control the virus long enough to get to something that could actually fix the underlying problem, which in this case was the transplant.
And I'll be honest, proceeding to transplant in a patient with active or recent PML was really frightening. And clearly that is not an option or appropriate at all for the majority of patients with PML. So I guess that the broader lesson here is that Virus-Specific T Cells or potentially other immune-facilitating strategies might serve as a bridge to get us to the point where we either have a way to address that root cause of immune suppression or just buy us the time needed to recover from immune suppressive exposures and perhaps opens up the question of how we might use sequential strategies and combinations of strategies to optimize the care of these patients.
Dr. Justin Abbatemarco:
Really appreciate your paradigm of how you think about these cases in treatment, and yet you can have these short-term strategies to bridge patients to have an improved immune response to get this under control. Could we talk about other common examples? So we have natalizumab-induced PML cases, HIV-associated PML cases. How would you think about managing those, so outside of these inborn errors of immunity?
Dr. Irene Cortese:
Each PML patient is somewhat unique, and definitely the underlying condition that is driving the immune suppressed state is really critical in mapping out what we need to do. I think of HIV-associated PML or even natalizumab-related PML as being somewhat unique. Because unlike most other causes of PML, we actually do have clear and reliable ways to restore immune competence, so basically antiretroviral therapy in HIV infection or simply discontinuing the non-immune-depleting drug natalizumab in the case of natalizumab-related PML. And so this is obviously a real advantage compared to many of the other underlying conditions where there really is no good way to reverse that immune suppression at all.
That said, in some patients, for example, with advanced AIDS and very low CD4 counts, immune reconstitution can still be very slow even when the HIV replication itself is well controlled. And so in a subset of patients, the PML can still really pace the recovery. And so we do sometimes need strategies to bridge that gap. And basically. we would consider the same immune restoration approaches that we've been talking about right now.
There is an added layer of complexity here that's a bit more, let's say, unique to HIV-related PML or to the setting of natalizumab-related PML, which is that in both these cases, immune reconstitution is going to happen eventually. And when it does, then many of those patients do experience PML IRIS where the constituting immune response paradoxically worsens the neurological injury by attacking the infected tissue. And so this really needs to be watched for and managed typically with steroids. And certainly this risk of developing PML IRIS needs to be really considered if we are going to use strategies to boost or facilitate immune reconstitution in the setting of HIV infection or natalizumab-related PML. And we just have to be particularly mindful because there's already a very high likelihood of developing PML IRIS independently of getting that extra boost.
Comparatively, in the setting of non-HIV-related PML or not in the setting of natilizumab treatment, I think that strategies like checkpoint inhibition and Virus-Specific T Cells have really been game-changing because, historically, these patients had no equivalent to antiretroviral therapy with no reliable path to reconstituting immunity. And we're really hoping that these approaches will start to bring the outcomes that we've seen, for example, among HIV-related PML and in the setting of natalizumab and PML to these other underlying conditions and achieve the same immune control and survival rates that are achieved in at least a substantial portion of these patients.
Dr. Justin Abbatemarco:
It's been so exciting. Again, the updates in this field when we really did... We had nothing to offer patients for so long and now to have conversations that are a little bit different. Can I ask you to peer around the corner? What does the future look like in your mind? Do you see other therapies that are potentially at play and maybe right now are there clinical trials that we could enroll patients so that we can help inform the field more broadly?
Dr. Irene Cortese:
Yeah. So I think that ways to facilitate and accelerate immune reconstitution have clearly been shown to be a valid strategy. And so what I expect and hope is that in the years to come, we'll learn to harness that better and learn to identify which patients are most likely to respond to particular types of strategies to facilitate immune reconstitution.
It's really important, I would say, that patients participate in trials because the field really does lack controlled data and it lacks head-to-head comparisons. And so every patient enrolled in a trial or a well-structured registry is really contributing to how the next patient gets treated. And given just how rare and heterogeneous PML is, we're just not going to advance this field through isolated case reports alone. And so we really do need patients and their physicians to be willing to participate in structured and collaborative research.
The Holy Grail is, of course, a direct antiviral agent that would really broaden our ability to treat patients and potentially also continue to treat whatever that underlying condition was that led them to the risk of PML in the first place, so, for example, patients receiving treatment for cancer or patients having an autoimmune disease that requires immune suppression. And so I am hopeful that eventually the direct antiviral will be identified.
And along that line, what I can mention is there are certainly clinical trials that are ongoing. At NIH, we have an active natural history study from where we can funnel patients into various experimental treatment strategies, including Virus-Specific T Cells or checkpoint inhibitors. Or right now, we actually do have an ongoing trial of intravenous brincidofovir as a possible direct antiviral strategy. What I hope for the future is that we will find ways to really collaborate and to form national as well as international consortia so that we can accelerate the development of these treatments.
Dr. Justin Abbatemarco:
We have things we can do now, and then we can help inform care for our future patients as well. So these are great messages, and I can't thank you enough for coming on. Again, most of these developments have been under your guidance, and we appreciate your leadership in this space and helping to give us this insight into this really rare disease. For folks, they can check out the article. It's in the New England Journal of Medicine, Resolution of TML After Treatment with Virus-Specific T Cells and HCT. Irene, thank you for coming on.
Dr. Irene Cortese:
Thank you so much.
Dr. Stacey Clardy:
This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org\podcast for our full list of past episodes, or you can also search by keyword on your podcast app for any neurology-specific topics.

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